My goals for this fellowship are focused on learning theoretical, practical, and conceptual approaches to solving a research problem that is immediately relevant to my clinical interests of neurology and neuropathology in the context of aging and neurodegenerative diseases. With a rapidly growing elderly population, learning about the mechanisms of neurodegeneration is crucial to treatment and preserving quality of life. I will become familiar with literature on the elderly and neurodegeneration. I want to practice and refine technical skills, such as stereotactic surgery, immunocytochemistry, computer programs, and statistics that are relevant to my research. Conceptually, I hope to gain a better understanding of the subcellular mechanisms that contribute to pathological processes and clinical presentations and use this knowledge for clinical trials with potential prophylactic or curative therapies. Finally, I hope to convey my knowledge to others through teaching and working in an academic setting. Any medicine or medical science must be done in both a basic research setting and in a clinical practice, and I want to bring these two areas together in my future career endeavors. The purpose of this research is to determine the contribution of free radicals to neurogeneration in elderly schizophremics. Beta amyloid, a toxic free radical generating peptide that frequently accumates in aged brain and is the likely cause of neuronal dealth in Alzheimer's Disease (AD), will be injected into the brains of transgenic mice and the resulting lesion will be quantitated using a computerized image analysis system. The first aim is to determine how altered expression of superoxide dismutase (SOD), an antioxidant enzyme, effects the size of beta amyloid lesions in SOD knockout mice and transgenic mice that overexpress SOD. The second aim is to investigate beta amyloid lesion characteristics in knockout mice that lack nitric oxide synthase (NOS), a pro-oxidant enzyme that makes the free radical NO. Brain will be immunocytochemically stained to assess lesion volumes. The distribution of oxidized proteins, lipids and DNA markers in the lesion will be determined. These experiments will test the hypothesis that age-related beta amyloid accumulation causes cognitive decline in elderly schizophrenics by exacerbating disease- related oxidative damage. With this added knowledge of disease mechanisms, prophylactic or curative therapies may be developed in the future.